Lung cancer staging consists of two parts: first, a determination of the location of the tumor and possible metastatic sites (anatomic staging), and second, an assessment of a patient's ability to withstand various antitumor treatments (physiologic staging). All patients with lung cancer should have a complete history and physical examination, with evaluation of all other medical problems, determination of performance status, and history of weight loss. The most significant dividing line is between those patients who are candidates for surgical resection and those who are inoperable but will benefit from chemotherapy, radiation therapy, or both. Staging with regard to a patient's potential for surgical resection is principally applicable to NSCLC.
Anatomic Staging of Patients with Lung Cancer
The accurate staging of patients with NSCLC is essential for determining the appropriate treatment in patients with resectable disease and avoiding unnecessary surgical procedures in patients with advanced disease (Fig. 89-4). All patients with NSCLC should undergo initial radiographic imaging with CT scan, positron emission tomography (PET), or preferably CT-PET. PET scanning attempts to identify sites of malignancy based on glucose metabolism by measuring the uptake of fluorodeoxyglucose F18. Rapidly dividing cells, presumably in the lung tumors, will preferentially take up 18F-FDG and appear as a "hot spot." To date, PET has been mostly used for staging and detection of metastases in lung cancer and in the detection of nodules >15 mm in diameter. Combined 18F-FDG PET-CT imaging has been shown to improve the accuracy of staging in NSCLC compared to visual correlation of PET and CT or either study alone. CT-PET has been found to be superior in identifying pathologically enlarged mediastinal lymph nodes and extrathoracic metastases. A standardized uptake value (SUV) of >2.5 on PET is highly suspicious for malignancy. False negatives can be seen in diabetes, in lesions <8 mm, in slow-growing tumors, and in concurrent infections such as tuberculosis. False positives can be seen in infections and granulomatous disease. Thus, PET should never be used alone to diagnose lung cancer, mediastinal involvement, or metastases. Confirmation with tissue biopsy is required. For brain metastases, MRI is the most effective method. MRI can also be useful in selected circumstances, such as for superior sulcus tumors, to rule out brachial plexus involvement, but in general does not play a major role in NSCLC staging.
Algorithm for management of non-small cell lung cancer.
In patients with NSCLC, the following are major contraindications to potential curative resection: extrathoracic metastases; superior vena cava syndrome; vocal cord and, in most cases, phrenic nerve paralysis; malignant pleural effusion; cardiac tamponade; tumor within 2 cm of the carina (potentially curable with combined chemoradiotherapy); metastasis to the contralateral lung; metastases to supraclavicular lymph nodes; contralateral mediastinal node metastases (potentially curable with combined chemoradiotherapy); and involvement of the main pulmonary artery. In situations where it will make a difference in treatment, abnormal scan findings require tissue confirmation of malignancy so that patients are not precluded from having potentially curative surgery.
The best predictor of metastatic disease remains a careful history and physical examination. If signs, symptoms, or findings from physical examination suggest the presence of malignancy, then sequential imaging starting with the most appropriate study should be performed. If the findings from the clinical evaluation are negative, then imaging studies beyond CT-PET are unnecessary and the search for metastatic disease is complete. More controversial is how one should assess patients with known stage III disease. Because these patients are more likely to have asymptomatic occult metastatic disease, current guidelines recommend a more extensive imaging evaluation, including imaging of the brain with either CT scan or MRI. In patients in whom distant metastatic disease has been ruled out, lymph node status needs to be assessed via a combination of radiographic imaging and/or minimally invasive techniques such as those mentioned above and/or invasive techniques such as mediastinoscopy, mediastinotomy, thoracoscopy, and thoracotomy. About a quarter to a half of patients diagnosed with NSCLC will have mediastinal lymph node metastases at the time of diagnosis. Lymph node sampling is recommended in all patients with enlarged nodes detected by CT or PET scan and in patients with large tumors or tumors occupying the inner third of the lung. The extent of mediastinal lymph node involvement is important in determining the appropriate treatment strategy: surgical resection followed by adjuvant chemotherapy versus combined chemoradiotherapy alone (see below). A standard nomenclature for referring to the location of lymph nodes involved with lung cancer has evolved (Fig. 89-5).
Lymph node stations in staging non-small cell lung cancer.
There are limited data on the use of CT-PET in the staging of patients with SCLC (Fig. 89-6). Current staging recommendations include a CT scan of the chest and abdomen (because of the high frequency of hepatic and adrenal involvement), MRI of the brain (positive in 10% of asymptomatic patients), and radionuclide (bone) scan if symptoms or signs suggest disease involvement in these areas. Bone marrow biopsies and aspirations are rarely performed given the low incidence of isolated bone marrow metastases. Confirmation of metastatic disease, ipsilateral or contralateral lung nodules, or metastases beyond the mediastinum may be achieved by the same modalities recommended above for patients with NSCLC.
Algorithm for management of small cell lung cancer.
If a patient has signs or symptoms of spinal cord compression (pain, weakness, paralysis, urinary retention), a spinal CT or MRI scan and examination of the cerebrospinal fluid cytology should be performed. If metastases are evident on imaging, a neurosurgeon should be consulted for possible palliative surgical resection and/or a radiation oncologist should be consulted for palliative radiotherapy to the site of compression. If signs of symptoms of leptomeningitis develop at any time in a patient with lung cancer, an MRI of the brain and spinal cord should be performed as well as a spinal tap for detection of malignant cells. If the spinal tap is negative, a repeat spinal tap should be considered. There is currently no approved therapy for the treatment of leptomeningeal disease.
The Staging System for Non-Small Cell Lung Cancer
The TNM International Staging System provides useful prognostic information and is used to stage all patients with NSCLC. The various T (tumor size), N (regional node involvement) and M (presence or absence of distant metastasis) are combined to form different stage groups (Table 89–5). The former tumor node metastasis (TNM) staging system for lung cancer (sixth edition) was developed based on a relatively small database of patients from a single institution. In 1999, the International Association for the Study of Lung Cancer established the lung cancer staging project and collected data on more than 68,000 cases from 46 sources in more than 19 countries to develop the new TNM (seventh edition) staging system, which has come into use as of 2010. As seen in Tables 89–5 and 89–6, the major distinction between the sixth and seventh edition staging system is within the T classification; T1 tumors are divided into tumors ≤2 cm in size, as these patients were found to have a better prognosis compared to tumors >2 cm but ≤3 cm. T2 tumors are divided into those that are >3 cm but ≤5 cm and those that are >5 cm but ≤7 cm. T3 tumors are >7 cm. T4 tumors include those that have additional nodules in the same lobe or tumors that have a malignant pleural effusion. No changes have been made to the current classification of lymph node involvement (N). Patients with metastasis may be classified as M1a, malignant pleural or pericardial effusion, pleural nodules or nodules in the contralateral lung, or M1b distant metastasis (e.g., bone, liver, adrenal, or brain metastasis). Based on these data, approximately one-third of patients have localized disease that can be treated with curative attempt (surgery or radiotherapy), one-third have local or regional disease that may or may not be amenable to a curative attempt, and one-third have metastatic disease at the time of diagnosis.
Table 89–5 Comparison of the Sixth and Seventh Edition TNM Staging Systems for Non-Small Cell Lung Cancer |Favorite Table|Download (.pdf)
Table 89–5 Comparison of the Sixth and Seventh Edition TNM Staging Systems for Non-Small Cell Lung Cancer
|Sixth Edition||Seventh Edition|
|T1||Tumor ≤3 cm diameter without invasion more proximal than lobar bronchus||Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion more proximal than lobar bronchus|
|T1a||Tumor ≤2 cm in diameter|
|T1b||Tumor >2 cm but ≤3 cm in diameter|
Tumor >3 cm diameter OR tumor of any size with any of the following:
Visceral pleural invasion
Atelectasis of less than entire lung
Proximal extent at least 2 cm from carina
Tumor >3 cm but ≤7 cm with any of the following:
Involves main bronchus, ≥2 cm distal to carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis extending to hilar region but not involving the entire lung
|T2a||Tumor >3 cm but ≤5 cm in diameter|
|T2b||Tumor >5 cm but ≤7 cm in diameter|
Tumor of any size that invades any of the following: chest wall, diaphragm, mediastinal pleura, parietal pericardium
Tumor <2 cm distal to carina
Tumor >7 cm or directly invades any of the following: chest wall (including superior sulcus tumors), phrenic nerve, mediastinal pleura, parietal pericardium
Tumor <2 cm distal to carina but without involvement of carina
Tumor with associated atelectasis or obstructive pneumonitis of entire lung
Separate tumor nodule(s) in same lobe
Tumor of any size that invades any of the following: mediastinum, heart or great vessels, trachea, esophagus, vertebral body, carina
Tumor with malignant pleural or pericardial effusion
Separate tumor nodules in same lobe
Tumor of any size that invades any of the following: mediastinum, heart or great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina
Separate tumor nodule(s) in a different ipsilateral lobe
|N0||No regional lymph node metastasis||No regional lymph node metastasis|
|N1||Metastasis in ipsilateral peribronchial and/or hilar lymph node(s)||Metastasis in ipsilateral peribronchial and/or hilar lymph node(s) and intrapulmonary node(s), including involvement by direct extensions|
|N2||Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)||Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)|
|N3||Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)||Metastasis in contralateral mediastinal, hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)|
|M0||No distant metastasis||No distant metastasis|
|M1||Distant metastasis (includes tumor nodules in different lobe from primary)||Distant metastasis|
Separate tumor nodules in a contralateral lobe
Tumor with pleural nodules or malignant pleural or pericardial effusion
Table 89–6 Comparison of Survival by Stage in TNM Sixth and Seventh Editions |Favorite Table|Download (.pdf)
Table 89–6 Comparison of Survival by Stage in TNM Sixth and Seventh Editions
|Stage||TNM Sixth Edition||TNM Seventh Edition||5-Year Survival (%)*|
Any T N3M0
T4 Any N M0
|IV||Any T Any N M1||Any T Any N M1a or M1b||13|
The Staging System for Small Cell Lung Cancer
Small cell lung cancer has a distinct two-stage system. Patients with limited-stage disease (LD) have cancer that is confined to the ipsilateral hemithorax and can be encompassed within a tolerable radiation port. Thus, contralateral supraclavicular nodes, recurrent laryngeal nerve involvement, and superior vena caval obstruction can all be part of limited-stage disease. Patients with extensive-stage disease (ED) have overt metastatic disease by imaging or physical examination. Cardiac tamponade, malignant pleural effusion, and bilateral pulmonary parenchymal involvement generally qualify disease as extensive-stage, because the involved organs cannot be encompassed safely or effectively within a single radiation therapy port. Sixty to 70% of patients are diagnosed with extensive disease at presentation.
Patients with lung cancer often have other comorbid conditions related to smoking, including cardiovascular disease and COPD. To improve their preoperative condition, correctable problems (e.g., anemia, electrolyte and fluid disorders, infections, cardiac disease, and arrhythmias) should be addressed, appropriate chest physical therapy instituted, and patients should be encouraged to stop smoking. Since it is not always possible to predict whether a lobectomy or pneumonectomy will be required until the time of operation, a conservative approach is to restrict surgical resection to patients who could potentially tolerate a pneumonectomy. Patients with an FEV1 (forced expiratory volume in 1 s) of greater than 2 L or greater than 80% of predicted can tolerate a pneumonectomy, and those with an FEV1 greater than 1.5 L have adequate reserve for a lobectomy. In patients with borderline lung function but a resectable tumor, cardiopulmonary exercise testing could be performed as part of the physiologic evaluation. This test allows an estimate of the maximal oxygen consumption (Vo2max). A Vo2max <15 mL/(kg·min) predicts for a higher risk of postoperative complications. Patients deemed unable to tolerate lobectomy or pneumonectomy from a pulmonary functional standpoint may be candidates for more limited resections, such as wedge or anatomic segmental resection, although such procedures are associated with significantly higher rates of local recurrence and a trend toward decreased overall survival. All patients should be assessed for cardiovascular risk using American College of Cardiology and American Heart Association guidelines. A myocardial infarction within the past 3 months is a contraindication to thoracic surgery because 20% of patients will die of reinfarction. An infarction in the past 6 months is a relative contraindication. Other major contraindications include uncontrolled arrhythmias, an FEV1 of less than 1 L, CO2 retention (resting PCO2 >45 mmHg), DLCO <40%, and severe pulmonary hypertension.
Treatment: Non-Small Cell Lung Cancer
The overall treatment approach to patients with NSCLC is shown in Fig. 89-4.
Management of Occult and Stage 0 Carcinomas
Patients with severe atypia on sputum cytology have an increased risk of developing lung cancer compared to those without atypia. In the uncommon circumstance where malignant cells are identified in a sputum or bronchial washing specimen but the chest imaging appears normal (TX tumor stage), the lesion must be localized. More than 90% of tumors can be localized by meticulous examination of the bronchial tree with a fiberoptic bronchoscope under general anesthesia and collection of a series of differential brushings and biopsies. Surgical resection following bronchoscopic localization improves survival compared to no treatment. Close follow-up of these patients is indicated because of the high incidence of second primary lung cancers (5% per patient per year).
Solitary Pulmonary Nodule and "Ground-Glass" Opacities
A solitary pulmonary nodule is defined as an x-ray density completely surrounded by normal aerated lung with circumscribed margins, of any shape, usually 1–6 cm at greatest diameter. The approach to a patient with a solitary pulmonary nodule is based on an estimate of the probability of cancer, determined according to the patient's smoking history, age, and characteristics on imaging (Table 89–7). Prior chest x-rays and CT scans should be obtained if available for comparison. A PET scan may be useful if the lesion is greater than 7–8 mm in diameter. If no diagnosis is apparent, Mayo Clinic investigators reported that clinical characteristics (age, cigarette smoking status, and prior cancer diagnosis) and three radiologic characteristics (nodule diameter, spiculation, and upper lobe location) were independent predictors of malignancy. At present, only two radiographic criteria are thought to predict the benign nature of a solitary pulmonary nodule: lack of growth over a period >2 years and certain characteristic patterns of calcification. Calcification alone, however, does not exclude malignancy; a dense central nidus, multiple punctate foci, and "bull's-eye" (granuloma) and "popcorn ball" (hamartoma) calcifications are highly suggestive of a benign lesion. In contrast, a relatively large lesion, lack of or asymmetric calcification, chest symptoms, associated atelectasis, pneumonitis, or growth of the lesion revealed by comparison with an old x-ray or CT scan or a positive PET scan are suggestive of a malignant process and warrant further attempts to establish a histologic diagnosis. An algorithm for assessing these lesions is shown in Fig. 89-3.
Table 89–7 Assessment of Risk of Cancer in Patients with Solitary Pulmonary Nodules |Favorite Table|Download (.pdf)
Table 89–7 Assessment of Risk of Cancer in Patients with Solitary Pulmonary Nodules
|Smoking status||Never smoker||Current smoker (<20 cigarettes/d)||Current smoker (>20 cigarettes/d)|
|Smoking cessation status||Quit ≥7 years ago or quit||Quit <7 years ago||Never quit|
|Characteristics of nodule margins||Smooth||Scalloped||Corona radiata or spiculated|
Since the advent of screening CTs, small GGOs have often been observed, particularly as the increased sensitivity of CTs enables detection of smaller lesions. Many of these GGOs, when biopsied, are found to be BAC. Some of the GGOs are semiopaque and referred to as "partial" GGOs. These are often more slow-growing and harbor atypical adenomatous hyperplasia histology, and are thought to be precursors to adenocarcinoma. By contrast, "solid" GGOs have faster growth rates and are usually typical adenocarcinoma histologically.
Management of Stages I and II NSCLC
Surgical Resection for Stages I and II NSCLC
Surgical resection by an experienced surgeon is the treatment of choice for patients with clinical stage I or II NSCLC who are able to tolerate the procedure. A retrospective review indicated that operative mortality rates for patients whose tumors were resected by noncardiothoracic or cardiothoracic surgeons were lower compared to general surgeons (5.8% vs 5.6% vs 7.6%, p = .001). The extent of resection is a matter of surgical judgment based on findings at exploration. A clinical trial in patients with stage IA NSCLC found that lobectomy was superior to wedge resection in reducing the rate of local recurrence, with a trend toward improvement in overall survival. A retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database also reported a survival benefit for lobectomy compared to wedge resection. A limited resection, wedge resection, and segmentectomy [potentially by video-assisted thoracic surgery (VATS)] may be more appropriate in patients with comorbidities, including compromised pulmonary reserve and small peripheral lesions. Pneumonectomy is reserved for patients with very central tumors and should only be performed in patients with excellent pulmonary reserve. The 5-year survival rates are 60–80% for patients with stage I NSCLC and 40–50% for patients with stage II NSCLC.
Accurate pathologic staging requires adequate segmental, hilar, and mediastinal lymph node sampling. Mediastinal lymph node dissection provides for a significantly larger amount of material, which can refine pathologic (nodal) stage. On the right side, mediastinal stations 2R, 4R, 7, 8R, and 9R should be dissected; on the left side, stations 5, 6, 7, 8L, and 9L should be dissected (Fig. 89-5). Hilar lymph nodes are typically resected and sent with the specimen, although it is helpful to specifically dissect and label level 10 lymph nodes when possible. On the left side, level 2 and sometimes level 4 lymph nodes are generally obscured by the aorta. Although the therapeutic benefit of nodal dissection versus nodal sampling remains controversial, in a recent pooled analysis of three trials, 4-year survival was superior in patients undergoing resection with stages I–IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling. Moreover, a complete mediastinal lymphadenectomy adds little morbidity to a pulmonary resection for lung cancer. Thus, the recommendation at this time is that patients should have a complete mediastinal node dissection.
Radiation Therapy in Stages I and II NSCLC
There is currently no role for adjuvant radiation therapy in patients following resection of stage I or II NSCLC. Patients with stage I or II disease who refuse or are not candidates for pulmonary resection should be considered for radiation therapy with curative intent. The decision to administer high-dose radiotherapy is based on the extent of disease and the volume of the chest that requires radiation. A systematic review reported 5-year survival rates of 13–39% in patients with stage I or II NSCLC treated with radical radiotherapy. Stereotactic radiation therapy and cryoablation are relatively new techniques that are being used in the treatment of patients with isolated pulmonary nodules who are not candidates for or refuse surgical resection, but their use may be limited by tumor size: ≤5 cm for stereotactic radiotherapy and ≤3 cm for cryoablation therapy.
Chemotherapy in Stages I and II NSCLC
A multitude of trials have evaluated the role of adjuvant chemotherapy in patients with resected stage IA–IIIA NSCLC with conflicting results (Table 89–8). A meta-analysis, the Lung Adjuvant Cisplatin Evaluation Study (LACE), reported a 5.4% improvement in 5-year survival for adjuvant chemotherapy compared to surgery alone in patients with stage I–IIIA NSCLC. The effect of cisplatin plus vinorelbine appeared marginally better than other cisplatin-based doublet regimens. The analysis, however, reported a harmful effect for chemotherapy in patients with stage IA disease, with questionable benefit in patients with stage IB disease. Chemotherapy also appeared to be detrimental in patients with poor performance status (ECOG PS2). The results of these studies have led to the recommendation for adjuvant chemotherapy only in patients with stage II or III NSCLC. Chemotherapy should start 6 to 8 weeks after surgery, if the patient has recovered, and should be administered for four cycles. All patients should be treated with a cisplatin-based regimen. Carboplatin is a reasonable consideration in patients who are unlikely to tolerate cisplatin for reasons such as reduced renal function, presence of neuropathy, or hearing impairment.
Table 89–8 Adjuvant Chemotherapy Trials in Non-Small Cell Lung Cancer |Favorite Table|Download (.pdf)
Table 89–8 Adjuvant Chemotherapy Trials in Non-Small Cell Lung Cancer
Cisplatin + vinorelbine
Cisplatin + vinorelbine
|CALGB||IB||Carboplatin + paclitaxel|
The treatment of patients with stage IB NSCLC remains controversial. Retrospective subset analyses of randomized phase III trials have reported no benefit for adjuvant chemotherapy in patients with stage IB disease. The only trial to evaluate adjuvant chemotherapy in patients with stage IB NSCLC reported no improvement in overall survival; however, a retrospective analysis of the trial reported a benefit in patients with tumors that were ≥4 cm. At this time, the risks and benefits of chemotherapy should be considered on an individual patient basis.
Four trials have evaluated neoadjuvant chemotherapy (chemotherapy before surgery) in patients with stage I–III NSCLC, of which three reported a trend toward improvement in progression-free and overall survival. However, at this time, no data support the use of neoadjuvant chemotherapy in NSCLC patients.
All patients with resected NSCLC are at high risk of recurrence or developing a second primary lung cancer. Thus, it is reasonable to follow these patients with regular imaging. The most appropriate modality and frequency has not been defined. Given that the majority of patients recur within the first 2 years after therapy, one guideline suggests CT scans of the chest with contrast every 6 months for the first 2 years after surgery, followed by yearly CT scans of the chest without contrast thereafter.
Management of Stage III NSCLC
The interpretation of the results of clinical trials involving patients with stage III NSCLC has been clouded by a number of issues, including changing diagnostic techniques, different staging systems, and heterogeneous patient populations. In prior studies, patients may have had tumors ranging from nonbulky stage IIIA (clinical N1 nodes with N2 nodes discovered only at the time of surgery, despite a negative mediastinoscopy) to bulky N2 nodes (lymph nodes >2 cm clearly visible on imaging, or multilevel ipsilateral mediastinal nodes) to clearly inoperable nodes.
Surgery followed by adjuvant chemotherapy is the treatment of choice for patients with stage IIIA disease due to hilar nodal involvement (T3N1). Surgery for N2 disease is more controversial. A randomized phase III trial demonstrated an improvement in progression-free survival but no improvement in overall survival when patients with pathologically staged N2 NSCLC were treated with concurrent chemoradiotherapy (cisplatin and etoposide) and 45 Gy of radiation followed by surgery compared to chemotherapy and 61 Gy of radiotherapy without surgery. Treatment-related mortality rate greater in the surgery arm (8% vs 2%), with the majority of deaths occurring in patients undergoing pneumonectomy. In subset analysis, the investigators found survival was improved if a lobectomy was performed but not pneumonectomy compared to chemoradiotherapy alone.
In spite of a careful preoperative staging evaluation, as many as a quarter of patients will be found to have metastases to N2 nodes on frozen-section examination at the time of thoracotomy or on final pathologic examination of the surgical specimen. For patients with an occult, single-station mediastinal node metastasis recognized at thoracotomy in which a complete resection of the nodes and primary tumor is technically possible, most thoracic surgeons proceed with the planned lung resection and a mediastinal lymphadenectomy. If a complete resection is not possible or there is multistation or bulky nodal disease or extracapsular nodal disease, then the planned lung resection should be aborted. These patients can then be considered for combined chemoradiotherapy as described below. Although incomplete resection rarely results in long-term survival, collected results indicate that surgery alone in stage IIIA disease (N2 disease) is associated with a 14–30% 5-year survival. The best survival rate is seen in cases with minimal N2 disease and complete resection.
Chemotherapy plus radiation therapy is the treatment of choice for patients with N3 nodal involvement or bulky stage IIIA disease. In general, patients with histologically involved lymph nodes >2 cm in short-axis diameter measured by CT, who have extranodal involvement or multistation disease along with groups of multiple smaller lymph nodes involved, are considered to have bulky, unresectable disease. Randomized phase III trials initially demonstrated an improvement in median and long-term survival for chemotherapy followed by radiation therapy, compared with radiation therapy alone. Subsequent trials demonstrated administering concurrent chemotherapy and radiation therapy results in improved survival compared to sequential therapy, albeit with more side effects, such as fatigue, esophagitis, and neutropenia. Therefore, combined modality treatment with chemotherapy and radiation therapy is recommended in patients who are able to tolerate the treatment.
Superior Sulcus or Pancoast Tumors
Superior sulcus tumors arise in the apex of the lung and invade adjacent structures producing Pancoast's syndrome: Horner's syndrome, shoulder and/or arm pain, and weakness and atrophy of the muscles of the hand. Patients with these tumors should undergo the same staging procedures as all patients with stage II or III NSCLC. Neoadjuvant chemotherapy or combined chemotherapy and radiation therapy is typically reserved for those patients with N0 or N1 involvement. This approach results in a 33-month median survival and 44% 5-year survival for all patients, and a 94-month median survival and 54% 5-year survival in patients with an R0 resection. For patients with Pancoast tumors that have metastatic disease at the time of presentation, radiation therapy with or without chemotherapy may be offered for palliation of symptoms.
Treatment of Metastatic Non-Small Cell Lung Cancer
Approximately two-thirds of NSCLC patients present with advanced disease (stage IIIB with a pleural effusion or stage IV) at the time of diagnosis. These patients have a median survival of 4–5 months and a 1-year survival of 10% when managed with best supportive care alone. In addition, a significant number of patients who present with early-stage NSCLC eventually relapse with distant disease. Patients who have recurrent disease have a better prognosis than those presenting with metastatic disease at the time of diagnosis. Standard medical management, the judicious use of pain medications, and the appropriate use of radiotherapy and chemotherapy form the cornerstone of management.
Chemotherapy palliates symptoms, improves the quality of life, and improves survival in patients with stage IV NSCLC, particularly in patients with good performance status. In addition, economic analysis has found chemotherapy to be cost-effective palliation for stage IV NSCLC. However, the use of chemotherapy for NSCLC requires clinical experience and careful judgment to balance potential benefits and toxicities.
First-Line Chemotherapy for Metastatic or Recurrent Non-Small Cell Lung Cancer
The first indication of the benefit of chemotherapy in patients with advanced NSCLC came from a meta-analysis published in 1995 that reported a survival advantage in patients treated with cisplatin-based chemotherapy compared to those receiving supportive care alone (HR = 0.73, p < .0001). This led to a multitude of clinical trials comparing different cisplatin-based regimens in patients with advanced NSCLC all reporting a similar magnitude of benefit; 20–30% response rate and an 8- to 10-month median survival (Table 89–9). Chemotherapy was well tolerated in all studies in patients with a good performance status, ECOG PS 0–1.
Table 89–9 First-Line Chemotherapy Trials for Metastatic Non-Small Cell Lung Cancer |Favorite Table|Download (.pdf)
Table 89–9 First-Line Chemotherapy Trials for Metastatic Non-Small Cell Lung Cancer
|Trial||Regimen||N||RR (%)||Median Survival (months)|
Cisplatin + paclitaxel
Cisplatin + gemcitabine
Cisplatin + docetaxel
Carboplatin + paclitaxel
Cisplatin + docetaxel
Cisplatin + vinorelbine
Carboplatin + docetaxel
Cisplatin + paclitaxel
Cisplatin + gemcitabine
Paclitaxel + gemcitabine
Cisplatin + gemcitabine
Carboplatin + paclitaxel
Cisplatin + vinorelbine
Cisplatin + vinorelbine
Carboplatin + paclitaxel
Cisplatin + irinotecan
Carboplatin + paclitaxel
Cisplatin + gemcitabine
Cisplatin + vinorelbine
Cisplatin + gemcitabine
Cisplatin + pemetrexed
Carboplatin + paclitaxel
An ongoing debate in the treatment of patients with NSCLC is the appropriate duration of platinum-based chemotherapy. Several large phase III randomized trials have failed to show a benefit for increasing the duration of platinum-based doublet chemotherapy beyond four to six cycles. In fact, longer duration of chemotherapy has been associated with increased toxicities and impaired quality of life. Therefore, prolonged therapy (beyond four to six cycles) with platinum-based regimens is not recommended in patients with advanced NSCLC.
Tumor histology has emerged as an important consideration in the treatment of patients with NSCLC. A randomized phase III trial found that patients with nonsquamous NSCLC had an improved survival when treated with cisplatin and pemetrexed compared to cisplatin and gemcitabine, while patients with squamous carcinoma had an improved survival when treated with cisplatin and gemcitabine. This difference in survival is thought to be related to the differential expression of thymidylate synthase, one of the targets of pemetrexed, between tumor types. Bevacizumab, a monoclonal antibody against VEGF, when combined with chemotherapy improves response rate, progression-free survival, and overall survival in patients with advanced disease (see below). However, bevacizumab cannot be given to patients with squamous cell histology NSCLC because of the risk of serious hemorrhagic effects.
Second-Line Chemotherapy and beyond
As first-line chemotherapy regimens improve, a substantial number of patients will maintain a good performance status and a desire for further therapy when they develop recurrent disease. At present only three drugs are FDA-approved for second-line therapy of NSCLC in the United States, i.e., docetaxel, pemetrexed, and erlotinib. In general, these agents have similar overall response rates of 5–10% (depending on the patient's prior exposure to taxanes and platinum) and yield median survivals of 6–8 months. However, the available drugs have distinct toxicity profiles that can influence their use in the second-line setting. Hematologic toxicity including febrile neutropenia is greater for docetaxel compared with pemetrexed and erlotinib, whereas nonhematologic toxicity, namely rash and diarrhea, is greater with erlotinib. Most of the survival benefit for any of these agents is realized in those patients who maintain a good performance status.
Agents that Inhibit Angiogenesis
Bevacizumab was the first antiangiogenic agent approved for the treatment of patients with advanced NSCLC in the United States. This drug primarily acts by sponging up VEGF and blocking the growth of new blood vessels, which are required for tumor viability. Two randomized phase III trials of chemotherapy with or without bevacizumab had conflicting results. The first trial, conducted in North America, compared carboplatin/paclitaxel with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in response rate, progression-free survival, and overall survival for chemotherapy-plus-bevacizumab–treated patients compared to chemotherapy alone. Toxicities were more frequent in bevacizumab-treated patients. The second trial, conducted in Europe, compared cisplatin/gemcitabine with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in progression-free survival but no improvement in overall survival for bevacizumab-treated patients. Therefore, at this time carboplatin/paclitaxel and bevacizumab is an approved regimen for first-line treatment of nonsquamous NSCLC in the United States but not in Europe.
Agents that Inhibit the Epidermal Growth Factor Receptor
Erlotinib and gefitinib are oral small-molecule kinase inhibitors that inhibit signaling via EGFR. These were the first EGFR inhibitors to be approved for the treatment of patients with NSCLC. A randomized phase III trial compared erlotinib to placebo in previously treated patients with advanced NSCLC and reported an improvement in overall survival for erlotinib compared to placebo. Gefitinib received premarketing approval by the FDA after impressive results seen in phase II trials in patients with previously treated NSCLC; however, a randomized phase III trial found no difference in overall survival between patients treated with gefitinib compared to placebo. These results led to a U.S. FDA-mandated change in the gefitinib indication to include only patients who have previously benefited from this drug. However, gefitinib is still available for the treatment of NSCLC patients in Europe and Asia. Clinical features that have been shown to correlate with responsiveness to EGFR TKI treatment include female sex, never smoking status, adenocarcinoma histology, and Asian ethnicity. Somatic mutations in the kinase domain of EGFR and high EGFR copy number have also been shown to correlate with response and improved survival with oral EGFR inhibitors.
Two randomized phase III trials conducted in Asia have compared gefitinib to platinum-based chemotherapy in patients with NSCLC. The first trial compared first-line gefitinib to carboplatin/paclitaxel in never or light ex-smokers with newly diagnosed advanced NSCLC. Treatment with gefitinib was associated with a significant improvement in response rate and 12-month progression-free survival. In patients with tumors available for mutation analysis, treatment with gefitinib was favored over chemotherapy in patients with tumors that harbored an EGFR mutation and chemotherapy was favored in patients with tumors that were EGFR mutation negative. Quality of life favored treatment with gefitinib. The second trial enrolled only patients with tumors that were EGFR mutation positive and reported a significant improvement in progression-free survival and disease control for patients treated with gefitinib compared to cisplatin/docetaxel. These and related results suggest standard chemotherapy regimens or gefitinib and erlotinib could be considered for first-line therapy in a subset of advanced NSCLC patients with tumors that harbor the EGFR mutation.
Cetuximab is an intravenously administered chimeric antibody directed against EGFR. A randomized phase III trial evaluated treatment with cisplatin/vinorelbine with or without cetuximab in patients with advanced NSCLC and at least one EGFR-positive cell as determined by immunohistochemistry. The results showed no difference in progression-free survival but a significant improvement in response rate and overall survival in patients treated with cetuximab compared to placebo. A prespecified subgroup analysis showed no improvement in overall survival among patients of Asian ethnicity receiving cetuximab compared with placebo. However, a significant improvement in overall survival was noted among Caucasian patients receiving cetuximab; this appeared true regardless of histology. Contrary to patients with colon cancer, KRAS mutation status did not predict response to therapy with cetuximab, although the number of cases examined at the molecular level was suboptimal. Development of acneiform rash was associated with improved overall survival compared to patients with no rash. A second phase III trial in patients with advanced NSCLC with no required EGFR testing reported no difference in overall survival between patients randomized to carboplatin/paclitaxel or docetaxel with or without cetuximab.
Maintenance chemotherapy in nonprogressing patients (patients with a complete response, partial response, or stable disease) is a controversial topic in the treatment of NSCLC patients. Two studies have investigated maintenance single-agent chemotherapy with docetaxel or pemetrexed in nonprogressing patients following treatment with first-line platinum-based chemotherapy. Both trials randomized patients to immediate single-agent therapy versus observation and reported improvements in progression-free and overall survival. In both trials, a significant portion of patients in the observation arm did not receive therapy with the agent under investigation upon disease progression; 37% of study patients never received docetaxel in the docetaxel study and 81% of patients never received pemetrexed in the pemetrexed study. In the trial of maintenance docetaxel versus observation, survival was identical to the treatment group in the subset of patients who received docetaxel on progression, indicating this is an active agent in NSCLC. These data are not available for the pemetrexed study. Currently maintenance pemetrexed is the only therapy approved by the U.S. FDA following platinum-based chemotherapy in patients with advanced NSCLC. However, maintenance chemotherapy is not without toxicity and at this time should be considered on an individual patient basis.
Two randomized controlled trials have reported improvements in progression-free survival from maintenance treatment with erlotinib compared to placebo in patients with advanced NSCLC following platinum-based chemotherapy.
Treatment: Small Cell Lung Cancer
Treatment of Limited Disease Small Cell Lung Cancer
SCLC is a highly aggressive disease characterized by its rapid doubling time, high growth fraction, early development of disseminated disease, and dramatic response to first-line chemotherapy and radiation. Surgical resection is not routinely recommended for patients because even those patients with LD-SCLC still have occult micrometastases. If the histologic diagnosis of SCLC is made in patients on review of a resected surgical specimen, such patients should receive standard SCLC chemotherapy as described below. If one employs classic TNM staging categories, two retrospective series have reported high cure rates for adjuvant chemotherapy following resection in patients with stage I or II SCLC.
Chemotherapy significantly prolongs survival in patients with SCLC. Combination chemotherapy with a platinum agent (cisplatin or carboplatin) and etoposide for four to six cycles is the mainstay of treatment and has not changed in almost three decades. Cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) may be an alternative for patients who are unable to tolerate a platinum-based regimen. Despite response rates to first-line therapy as high as 80%, the median survival ranges from 12 to 20 months for patients with LD and from 7 to 11 months for patients with ED. Regardless of disease extent, the majority of patients relapse and develop chemotherapy-resistant disease. Only 6–12% of patients with LD- and 2% of patients with ED-SCLC live beyond 5 years. The prognosis is especially poor for patients who relapse within the first 3 months of therapy; these patients are said to have platinum-resistant disease. Patients are said to have sensitive disease if they relapse more than 3 months after their initial therapy and are thought to have a somewhat better overall survival. Those patients with sensitive disease are thought to have the greatest potential benefit from second-line chemotherapy. Topotecan is the only FDA-approved agent with modest activity as second-line therapy in patients with SCLC.
Patients with LD-SCLC are treated with combined modality therapy with cisplatin and etoposide chemotherapy and radiation therapy. A retrospective analysis of patients with SCLC treated with once-daily fractionation found improved local control rates as the total dose delivered was increased from 30 to 50 Gy. Chemotherapy when given concurrently with radiation is more effective than sequential chemoradiation but is associated with significantly more esophagitis and hematologic toxicity. The addition of radiation therapy early on is preferred. Twice-daily (hyperfractionated) radiation has been shown to improve survival in patients with LD-SCLC but is associated with higher rates of grade 3 esophagitis and pulmonary toxicity. It is feasible to deliver once-daily radiation therapy doses up to at least 70 Gy when administered concurrently with cisplatin-based chemotherapy. This higher dose of once-daily radiotherapy may be equivalent or superior to the 45-Gy twice-daily radiotherapy dose. Patients should be carefully selected for concurrent chemoradiation therapy based on good performance status and pulmonary reserve.
Prophylactic Cranial Irradiation
Prophylactic cranial irradiation (PCI) should be considered in all patients with LD- and ED-SCLC who have responded to initial therapy. A meta-analysis including 7 trials and 987 patients with LD-SCLC who had achieved a complete remission following primary chemotherapy reported a 5.4% improvement in overall survival for patients treated with PCI. In patients with ED-SCLC who had responded to first-line chemotherapy, PCI reduced the occurrence of symptomatic brain metastases and prolonged disease-free and overall survival compared to no radiation therapy. Long-term toxicities including deficits in cognition have been reported following PCI and are difficult to sort out from the effects of chemotherapy or normal aging.
Molecularly Tailored Lung Cancer Therapy
In the past 40 years, clinical research in lung cancer has demonstrated that surgery, systemic chemotherapy, and radiation therapy can all be used to prolong patient survival and/or improve quality of life. However, conventional approaches, especially those that classify patients according to disease histology alone, appear to have reached a therapeutic plateau of effectiveness. One promising future approach to improve the outcome for patients with lung cancer is tailored therapy based on individualized phenotypic or genotypic tumor characteristics. Such a strategy is based upon an understanding of the molecular underpinnings of the disease, recognizing that although tumors may appear similar at the histologic level, they do differ from individual to individual. It is hoped that better outcomes can be achieved by matching the most appropriate therapy to a patient at the right time.
For example, one subset of lung cancer can be defined by somatic mutations in EGFR. EGFR mutations are almost exclusively found in lung adenocarcinoma and are more common in females, never smokers compared to former or current smokers, and in East Asians compared to Western populations (30–70% vs 8%). These mutations, primarily in-frame deletions in exon 19 and point mutations in exon 21 (L858R), result in constitutive activation of the receptor and are associated with very high response rates (60–90%) to the specific tyrosine kinase inhibitors gefitinib and erlotinib. Almost all patients with these dramatic responses, however, develop acquired resistance. In about half of patients, resistance can be attributed to the emergence of clones harboring a second-site mutation in exon 20 (T790M), which alters binding of drug to the receptor. About 20% of EGFR mutant tumors from patients with acquired resistance display amplification of a gene encoding a different tyrosine kinase, MET. As a result of these findings, many trials are being conducted in these patients using second-generation EGFR inhibitors that can overcome T790M-mediated resistance or MET inhibitors to target MET-dependent cells.
Another subset of lung adenocarcinoma can be defined by EML4-ALK fusion proteins. These translocations arise from a small inversion within chromosome 2p that leads to the formation of a fusion-gene comprising the N terminal of the echinoderm microtubule–associated protein-like 4 (EML4) gene and the intracellular tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) gene. Patients with lung cancers harboring an ALK fusion protein have demonstrated dramatic responses to small-molecule ALK inhibitors in early clinical trials. The ALK fusion protein is relatively rare, occurring in 3–7% of NSCLCs. Clinical characteristics associated with EML4-ALK–positive lung cancer appears to be a younger age at diagnosis, minimal smoking history, male sex, and adenocarcinoma histology with signet-ring features.
Other biomarkers being explored include molecules that may predict outcomes with conventional chemotherapy. For example, low expression of the DNA repair gene excision repair cross-complementation group 1 (ERCC1) correlates with improved survival after treatment with platinum drugs, whereas tumors that have high expression of ERCC1 are less sensitive to therapy with a platinum agent. In the absence of treatment, lung cancer with low ERCC1 expression has a poorer prognosis.
Ribonucleotide reductase M1 (RRM1) encodes the regulatory subunit of ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. Ribonucleotide reductase converts ribonucleotide 5-diphosphate to deoxyribonucleotide 5-diphosphate. Notably, gemcitabine, an agent commonly used in the treatment of NSCLC, competes with ribonucleotide 5-diphosphate for incorporation into DNA. Levels of RRM1 expression are significantly and inversely correlated with disease response after two cycles of gemcitabine and carboplatin in patients with locally advanced NSCLC. In addition, low RRM1 mRNA expression levels are associated with a significantly longer median survival compared to high levels.
Thymidylate synthase (TS) catalyzes the methylation of dUMP to dTMP and is the rate-limiting irreversible step in de novo DNA synthesis. TS is one of the targets of the novel folate-based drug pemetrexed, an agent that is FDA-approved as second-line treatment in patients with NSCLC. TS expression is an independent prognostic and predictive factor in several cancers, including lung cancers, and overexpression of TS has been linked to resistance to pemetrexed, an agent commonly employed as second-line treatment in patients with nonsquamous NSCLC. TS mRNA and protein levels are significantly higher in squamous cell carcinomas and small cell carcinomas of the lung as compared with adenocarcinomas. A randomized phase III trial reported that cisplatin plus gemcitabine was more effective in squamous cell carcinomas while, cisplatin plus pemetrexed was found to be more effective in adenocarcinomas and large cell carcinomas. Molecular markers are likely to play an increasing role in helping guide treatment decisions.